Investigations into the mechanisms underlying the increase in glucose-dependent insulin secretion during DHA/EPA stimulation in pancreatic beta cells.

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K18997
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General physiology
• Research Institution: University of Fukui (2017-2018); Ritsumeikan University (2016)
• Principal Investigator: Takeda Yukari 福井大学, 学術研究院医学系部門, 助教 (20582159)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 受容体・細胞内シグナル伝達

Outline of Final Research Achievements

Activation of GPR40 by long-chain fatty acids, EPA and DHA, increase glucose-stimulated insulin secretion from pancreatic beta cells. The current study demonstrated that simultaneous activation of GPR40 and GLP-1 receptor (R) signal transduction cascades (PKC pathway and PKA pathway) synergistically increased insulin secretion from INS-1. The effect was completely abolished by a PKA inhibitor, H-89 alone, suggesting crosstalk between GPR40 and GLP-1R signaling systems. Interestingly, the insulinotropic effect of PKC is also inhibited by H-89. It indicates that pre-phosphorylation of the PKC effector by PKA at a basal cAMP level, is fundamental to the PKC effect. Mathematical analysis suggested that IP3R is the key target effector of the crosstalk between GPR40 and GLP-1 receptor (R) signaling pathways.

Free Research Field

医歯薬学

Academic Significance and Societal Importance of the Research Achievements

二型糖尿病患者が世界的に増加の一途をたどる中、GPR40刺激が血糖値依存的にインスリン分泌を増強することから、二型糖尿病治療の新たな薬剤標的として近年注目を浴びている。一方で、武田薬品工業が生成したGPR40合成作動薬TAK-875は、肝機能異常を伴うため新たな薬剤の探索が急務であるとされていた。本研究ではIP3Rが二型糖尿病治療の新たな標的となる可能性を示した。また、GLP-1R・GPR40シグナル伝達系の同時刺激よるIP3Rの相乗的な活性化は、魚類などEPAを多く含む食事療法やサプリメントの摂取で実現できる可能性があり、安心・安全な糖尿病治療に貢献できると期待する。